Abstract Successful tuberculosis vaccine development is critically dependent on identifying host factors that protect against the development of active tuberculosis (TB). The immunologic components that prevent disease development are incompletely understood, especially during the early stages of infection. While cell-mediated immunity has been extensively studied, the role of antibodies (Abs) remains less explored. In recent years, various studies have provided increasing evidence for a role of Ab-mediated immunity against TB including compelling evidence for protective systemic Ab functions in humans with latent (LTBI) compared to active TB. However, little is known about the involvement and timing of Ab responses at the local level of M. tuberculosis (Mtb) infection but studies suggest that early events could impact the outcome of infection. Identifying potentially protective Ab profiles against specific immunogenic Mtb antigens would fill a gap in knowledge and could contribute to the better understanding of early immune responses in Mtb infection. Cynomolgus macaques infected with low-dose Mtb develop latent infection and TB in equal proportion. Unlike most other models, this model provides a unique opportunity to examine immunologic factors that could influence the outcomes of infection similar to those in humans. Based on our preliminary data with samples from Mtb infected macaques, our overall hypothesis is that Abs against certain Mtb antigens are associated with the lack of TB development in natural infection. We propose to evaluate a spectrum of humoral immune responses in Mtb infected nonhuman primates (NHPs) in an unbiased approach with the goal of identifying Ab profiles that are associated with controlled LTBI. We have banked serial samples of plasma and broncho-alveolar lavage fluid from animals with defined latent and active infection. With these samples, we will address the following Aims: 1. To investigate mucosal airway Ab responses elicited by airway Mtb infection; and 2. To identify systemic Ab patterns that are associated with lack of TB development. Identifying potentially protective Abs to specific immunogenic Mtb antigens would fill a gap in knowledge, and could inform vaccine development. Our proposed short term plan is to identify novel Ab targets that correlate with lack of TB development in natural infection (this current proposal). Our long term plan is to generate monoclonal Abs (mAbs) to a spectrum of potentially protective Mtb antigens, study their functions, and assess their protective efficacy in vivo. The proposed studies have a high likelihood of success given the expertise of the investigators, the promising preliminary data, the unique assays used, and the availability of stored well-characterized NHP samples.